| Size | Price | Stock | Qty |
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| 100mg |
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| 250mg |
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| 500mg | |||
| Other Sizes |
| Targets |
SSRI; tricyclic antidepressant (TCA)
Azaphen targets monoamine transporters, particularly the serotonin transporter (SERT) and norepinephrine transporter (NET), inhibiting the reuptake of serotonin and norepinephrine. It may also antagonize histamine, muscarinic, and adrenergic receptors. |
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| ln Vitro |
Pipofezine Dihydrochloride Monohydrate 2 [1]
The MicroED structure 2 was solved in a monoclinic P 21/c space group at the resolution of 0.82 Å (Figure 2b and Figure 3), with the unit cell parameters of a = 6.88 Å, b = 15.61 Å, c = 15.93 Å, α = 90.0°, β = 97.2°, γ = 90.0°. Two conforms, namely 2a and 2b were identified in the uniFig t cell. Each can be transformed by inversion symmetry or 180° rotation of C11‒N4/C11′‒N4′ bond. The crystal packing is formed mainly by hydrogen bonds and ion-dipole interactions between 2a/2b and chloride anions along b- and c-axes, i.e. hydrogen bonds N5/N5′─H···Cl1 (3.01 Å) and N3/N3′─H···O2 (2.67 Å); ion-dipole interactions between CH atoms and chloride anions (Figure S3, Supporting Information). The water molecules serve as hydrogen bond donors to Cl1 or Cl2 anions that bridge 2a and 2b molecules together (Figure S3, Supporting Information). The packing along the a-axis is facilitated by strong parallel-displaced pi-stacking interactions between the phenyl and pyridazine rings in 2a and 2b (3.65 Å). In 2, bond angles are mostly fixed, with only one freely rotating bond (C10‒C11‒N4‒C15 and C10′‒C11′‒N4′‒C15′, measured at ±178.60° in 2a and 2b), generating a co-planar arrangement of piperazine ring and tricyclic moiety (Figure S4, Supporting Information).[5]
Azaphen inhibits the reuptake of serotonin and norepinephrine, increasing their synaptic concentrations and enhancing monoaminergic neurotransmission. It exhibits antidepressant activity in animal models and was used clinically for the treatment of depression. |
| ln Vivo |
In vivo, Azaphen demonstrates antidepressant efficacy in animal models of depression such as the forced swim test and tail suspension test. It increases monoamine levels in the brain and ameliorates depressive-like behaviors.
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| Enzyme Assay |
2‒hSERT Complexes[1]
2 was tested at the central (S1) and allosteric (S2) sites in hSERT (Figure S12c, Supporting Information),[32] however the final docking center was found near S2 site due to the weak binding observed in S1 site (i.e., only the hydrophobic interactions). A salt bridge between Asp98 and piperazine ring, together with one pi-stacking (Phe335), one pi-cation interaction (Arg104), and three hydrophobic interactions (Phe335, Phe556) to the tricyclic moiety stabilized the binding complex of 2/hERT (Figure 4c). The structures of 2 in its drug-formulation state and biologically active state are very similar, with only 3–6° rotation C11′‒N4′ bond (Figure S4, Supporting Information), and maintain the piperazine ring and tricyclic moiety in a nearly co-planar geometry (C10‒C11‒N4‒C15≈180°) for both states. The minimum conformational changes ensure small entropy differences upon binding which is beneficial for the binding of 2 to the receptor.
In vitro enzyme/receptor binding assays for Azaphen involve radioligand binding studies to determine affinity for SERT, NET, and various receptors. Inhibition of [³H]-serotonin or [³H]-norepinephrine uptake in synaptosomes or cell lines expressing transporters is measured to determine reuptake inhibition potency. |
| Cell Assay |
In vitro cell-based assays for Azaphen use neuronal cell lines or primary neurons to study monoamine uptake inhibition. Cells are treated with Azaphen and incubated with radiolabeled serotonin or norepinephrine, and uptake is measured by scintillation counting. Receptor binding assays use membrane preparations from cells expressing target receptors.
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| Animal Protocol |
In vivo animal studies for Azaphen employ rodent models of depression such as the forced swim test, tail suspension test, or learned helplessness. Azaphen is administered orally or intraperitoneally, and behavioral parameters are assessed to determine antidepressant efficacy. Brain monoamine levels are measured by HPLC.
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| ADME/Pharmacokinetics |
Azaphen dihydrochloride monohydrate has a molecular weight of approximately 335 g/mol. As a tricyclic antidepressant, it is expected to be well-absorbed orally, highly protein-bound, extensively metabolized in the liver, and excreted renally. It has a relatively long half-life.
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| Toxicity/Toxicokinetics |
Azaphen, as a tricyclic antidepressant, has a side-effect profile similar to other TCAs, including anticholinergic effects (dry mouth, constipation, blurred vision), sedation, cardiotoxicity, and potential for overdose toxicity. It may cause weight gain and sexual dysfunction.
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| References |
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| Additional Infomation |
Most treatments for major depressive disorder work by inhibiting human monoamine transporters (which are essential for the reuptake of monoamine neurotransmitters) or by inhibiting monoamine oxidases (which are essential for the degradation of monoamine neurotransmitters). Analyzing the experimental three-dimensional structures of these antidepressants in their pharmaceutical formulations is crucial for precise drug design and development. This study is the first to use microcrystalline electron diffraction (MicroED) to resolve the atomic-level three-dimensional structures of five of the most commonly used antidepressants (reboxetine, piperazine, amisulfosine, phenelzine, and bifemyllan) directly from commercially available active ingredient powders. Their binding modes were studied by molecular docking, revealing key interactions and conformational changes in the biologically active state. This study highlights the importance of combining MicroED and molecular docking in revealing elusive drug structures and mechanisms, which can contribute to further drug development. [1]
Azaphen is a tricyclic antidepressant that was used clinically for the treatment of depression. It is structurally related to other TCAs such as imipramine and amitriptyline. Its use has largely been superseded by newer antidepressants with more favorable side-effect profiles. Not currently widely used. |
| Molecular Formula |
C16H23CL2N5O2
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|---|---|
| Molecular Weight |
388.2921
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| Exact Mass |
387.122
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| CAS # |
63302-99-8
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| Related CAS # |
Azaphen;24853-80-3
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| PubChem CID |
2728833
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| Appearance |
Light yellow to green yellow solid powder
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
1
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| Heavy Atom Count |
25
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| Complexity |
387
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| Defined Atom Stereocenter Count |
0
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| SMILES |
CN1CCN(CC1)C2=NN=C3C(=C2)N(C4=CC=CC=C4O3)C.O.Cl.Cl
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| InChi Key |
VKMOGSQJNTXLNA-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C16H19N5O.2ClH.H2O/c1-19-7-9-21(10-8-19)15-11-13-16(18-17-15)22-14-6-4-3-5-12(14)20(13)2;;;/h3-6,11H,7-10H2,1-2H3;2*1H;1H2
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| Chemical Name |
5-methyl-3-(4-methylpiperazin-1-yl)pyridazino[3,4-b][1,4]benzoxazine;hydrate;dihydrochloride
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| Synonyms |
63302-99-8; Azaphen dihydrochloride monohydrate; Azaphen (dihydrochloride monohydrate); Azaphenonxazine dihydrochloride monohydrate; 5-Methyl-3-(4-methylpiperazin-1-yl)-5H-benzo[B]pyridazino[4,3-E][1,4]oxazine dihydrochloride hydrate; 5-methyl-3-(4-methylpiperazin-1-yl)pyridazino[3,4-b][1,4]benzoxazine;hydrate;dihydrochloride; Azafen dihydrochloride monohydrate; Cambridge id 5175311;
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
H2O : ≥ 100 mg/mL (~257.54 mM)
DMSO : ~1 mg/mL (~2.58 mM) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: 50 mg/mL (128.77 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication.
(Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.5754 mL | 12.8770 mL | 25.7539 mL | |
| 5 mM | 0.5151 mL | 2.5754 mL | 5.1508 mL | |
| 10 mM | 0.2575 mL | 1.2877 mL | 2.5754 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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